The Effects of Acamprosate and Neramexane on Cue-Induced Reinstatement of Ethanol-Seeking Behavior in Rat

Abstract

This study examines, for the first time, the effects of acamprosate and the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist neramexane on ethanol-seeking induced by alcohol-related environmental stimuli in an animal model of relapse. Wistar rats were trained to operantly self-administer ethanol (10% w/v) or water on a fixed-ratio 1 schedule in a 30-min daily session. Ethanol availability was signaled by an olfactory discriminative stimulus of orange extract (S þ ). In addition, each lever press was accompanied by a 5-s illumination of the operant chamber's house light (CS þ ). Water availability was signaled by anise odor (S À ) and 5-s white noise stimulus (CS À ). After completion of the conditioning phase, indicated by stable levels of responding, operant behaviors were extinguished. Prior to reinstatement tests, animals were divided into groups according to either treatment with acamprosate (100, 200 mg/kg given twice), neramexane (1.0, 2.0, 4.0 mg/kg), or vehicle. In vehicle-treated rats, re-exposure to the S þ /CS þ in the absence of further ethanol availability elicited strong recovery of responding. No effect was observed following presentation of water-paired cues (S À /CS À ). Acamprosate dose-dependently attenuated recovery of responding elicited by ethanol-paired cues (S þ /CS þ ), whereas responding under S À /CS À was not modified by drug administration. Treatment with 1.0 and 2.0 mg/kg of neramexane did not significantly modify responding under both S þ /CS þ and S À /CS À conditions. However, a slight reduction of cue-induced reinstatement of alcohol seeking was observed. At the dose of 4.0 mg/kg, neramexane elicited a marked inhibition of responding following presentation of both ethanol-and water-paired cues. In conclusion, acamprosate significantly and selectively reduced alcohol-seeking elicited by environmental stimuli predictive of alcohol availability. Treatment with neramexane that shares part of the pharmacological effects of acamprosate on NMDA receptors, however, resulted in a nonselective reduction of lever responding.

Relapse to drug seeking following prolonged abstinence: the role of environmental stimuli

“…Acamprosate and naltrexone, FDA-approved medications that promote abstinence in alcohol abusers [24,25 ], dose-dependently attenuate ethanol seeking in response to the S + /CS + without altering responding to the S − /CS − [23,26 ]. These findings support the predictive validity of this paradigm, as a model of cue-induced ethanol relapse.…”

Acamprosate Produces Its Anti-Relapse Effects Via Calcium

“…Reinstatement of alcohol-seeking is used to study the neurobiological and molecular basis of craving, as there appears to be a good correspondence between the events that induce alcohol-seeking in laboratory animals and those that provoke craving in humans (Shaham et al, 2003). In a previous study, it was shown that acamprosate completely abolishes the cue-induced reinstatement response (Bachteler et al, 2005). As described in this previous report, the calcium salt of N-acetylhomotaurinate (acamprosate) abolished the reinstatement response but equimolar concentration of the corresponding sodium salt formulation of acamprosate had no effect (Figure 4).…”

Influence of reinforcement schedule on ethanol consumption patterns in non-food restricted male C57BL/6J mice

“…Extinction of ethanol-reinforced responding was performed as previously described for rats (Bachteler et al, 2005) and mice (Tsiang and Janak, 2006). After mice responded on the RR8 schedule for 16 weeks, the animals were exposed to 30-min extinction sessions during which both levers were extended and the house light remained illuminated.…”